Exendins and Exendin Agonists Modified with Polyamino Acids

• US 20080200390A1
• Filed: 04/11/2008
• Published: 08/21/2008
• Est. Priority Date: 04/30/1999
• Status: Active Grant

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Young, Andrew A., PRICKETT, Kathryn S.
• Granted Patent: US 7,691,963 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Novel modified exendins and exendin agonists having an exendin or exendin agonist linked to one or more molecular weight increasing compounds, for example, polyamino acids, polyethylene glycol polymers, and related formulations and dosages and methods of administration thereof are provided. These modified exendins and exendin agonists, compositions and methods are useful in treating diabetes and conditions that would be benefited by lowering plasma glucose or delaying and/or slowing gastric emptying or inhibiting food intake.

Claims

1. A compound comprising exendin-4 linked to a polylysine through a C-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2 or 51.

2. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to a polylysine through a C-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2 or 51; and

(B) a pharmaceutically acceptable carrier.

3. The pharmaceutical composition of claim 2, wherein the C-terminal amino acid is lysine.

4. A kit comprising the pharmaceutical composition of claim 2 and instructions for use.

5. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to a polylysine through (i) a C-terminal amino acid on the exendin-4, (ii) an internal lysine amino acid on the exendin-4, (iii) an internal aspartic acid amino acid on the exendin-4, (iv) an internal glutamic acid amino acid on the exendin-4, (v) an internal cysteine amino acid on the exendin-4, or (vi) an N-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2 or 51; and

(B) a pharmaceutically acceptable carrier.

6. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the C-terminal amino acid on the exendin-4.

7. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the internal lysine amino acid on the exendin-4.

8. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the internal aspartic acid amino acid on the exendin-4.

9. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the internal glutamic acid amino acid on the exendin-4.

10. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the internal cysteine amino acid on the exendin-4.

11. The pharmaceutical composition of claim 5, wherein the exendin-4 is linked to the polylysine through the N-terminal amino acid on the exendin-4.

12. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to a polyamino acid through a C-terminal amino acid on the exendin-4;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2 or 51; and

(B) a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, wherein the polyamino acid is polylysine.

14. The pharmaceutical composition of claim 12, wherein the polyamino acid is polyglutamic acid.

15. The pharmaceutical composition of claim 12, wherein the polyamino acid is polyaspartic acid.

16. The pharmaceutical composition of claim 12, wherein the C-terminal amino acid is lysine.

17. A pharmaceutical composition comprising (A) a compound which comprises exendin-4 linked to a polyamino acid through (i) a C-terminal amino acid, (ii) an internal lysine amino acid, (iii) an internal aspartic acid amino acid, (iv) an internal glutamic acid amino acid, (v) an internal cysteine amino acid, or (vi) an N-terminal amino acid;

wherein the exendin-4 comprises the amino acid sequence of SEQ ID NO;

2 or 51; and

(B) a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, wherein the polyamino acid is polylysine.

19. The pharmaceutical composition of claim 17, wherein the polyamino acid is polyglutamic acid.

20. The pharmaceutical composition of claim 17, wherein the polyamino acid is polyaspartic acid.